DESCRIPTION (from the application): Alzheimer's Disease ( AD) is characterized by the formation of amyloid plaques and cerebrovascular amyloid deposits, the principal component of which is the ~ 4 kDa amyloid peptide (ABeta). ABeta is derived from a large transmembrane precursor, the amyloid precursor protein (APP), the physiological function of which remains to be elucidated. In the previous 4 years, we have focused on studies of proteins that interact with the C-terminal domain of APP (APPc), and on the phosphorylation of APP. These studies have identified the adaptor protein, FE65, as an important regulator of APP localization and processing. We have also identified Cdk5 as a major kinase responsible for phosphorylation of APPc in neurons, and found that phosphorylation of APP by Cdk5 regulates neurite outgrowth in model neuronal cell lines. The Long-term objectives of this part of the Program Project application are to continue to analyze the regulation of APP by its interaction with the adaptor protein, FE65, and via phosphorylation by Cdk5. Specific aims of the project are: Aim 1. To characterize the interaction between APP and FE65. These studies will examine the influence of FE65 on APP processing, and will examine the localization of APP, FE65 and associated proteins in neurons. Aim 2. To characterize the phosphorylation of APP by Cdk5. These studies will examine the regulation of Cdk5 activity and phosphorylation of APP in intact neurons, the effects of phosphorylation of Thr668 on APP processing, and the structural consequences of phosphorylation of Thr668. Aim 3. To characterize the regulation of Cdk5. These studies will examine the phosphorylation and dephosphorylation of the catalytic subunit of Cdk5, the phosphorylation and dephosphorylation of the regulatory, p35 and p25, subunits of Cdk5, and the interaction of p35/p25 with the Cdk5 catalytic subunit. The proposed studies should contribute to a greater understanding of signal transduction mechanisms involved in APP processing and APP function, and the contributions these make to AD.